There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in systemic autoimmune disease. Recent studies have determined that innate immunity plays an indispensable role in both idiopathic and environmentally induced systemic autoimmunity. The parent R01 grant addresses the overarching hypothesis that distinct components of the innate immune system regulate the severity of systemic autoimmunity induced by specific xenobiotics. The aims of this ViCTER application expand the scope of the interdisciplinary nature of the parent grant by engaging with experts in the fields of microRNAs and nanoparticles to add new insights into the role of the innate immune response in xenobiotic-induced autoimmunity and help determine if common or distinct mechanisms underlie development of disease. The third project seeks to determine if a therapeutic approach can regulate xenobiotic-induced autoimmunity via modulation of innate immune function. Although each research project is distinct, they have been specifically selected because their experimental approaches and/or findings can be applied to studies ongoing in the parent grant and/or in the ViCTER projects. The specific aims are as follows: Specific Aim 1: The contribution of nanoparticles and microRNAs to the role of the innate immune system in the induction of xenobiotic-induced autoimmunity. Studies in Project 1 (PI: Professor Holian, University of Montana) will expand the range of xenobiotics under investigation in the parent grant by examining the ability of nanoparticles to induce and/or exacerbate autoimmunity and examining potential mechanisms. In Project 2 (PI: Professor Chan, University of Florida) samples from the parent grant will be tested for their microRNA and associated gene expression profiles to determine if different xenobiotics elicit autoimmunity via common or unique pathways of microRNA regulated gene expression. Specific Aim 2: Regulation of xenobiotic-induced autoimmunity by anti-CD3 induced T regulatory cells (PI: Professor Pollard, The Scripps Research Institute). Although the parent grant for this ViCTER seeks greater understanding of the innate immune mechanisms responsible for environmentally-induced autoimmunity, no studies were proposed to explore specific therapeutic interventions. This subproject will examine whether anti-CD3 antibody induced T regulatory cells suppress autoimmunity induced by xenobiotics, whether this is augmented by CD55 costimulation, and if the mechanism requires IL-27 produced by dendritic cells. This ViCTER proposal builds on an established interdisciplinary program, including expertise in immunology, immunotoxicology, genetics and innate immunity by adding expertise in nanoparticles and pulmonary inflammation (Professor A. Holian, University of Montana) and microRNA (Professor E.K. Chan, University of Florida). This expansion of the interdisciplinary team provides a significantly broader base of knowledge to answer important questions regarding mechanisms of innate immunity underlying xenobiotic-induced systemic autoimmunity.